Self-Assembled Squalenoylated Penicillin Bioconjugates: An Original Approach for the Treatment of Intracellular Infections
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- 作者：Nicolas S茅miramoth ; Chiara Di Meo ; Fatima Zouhiri ; Fatouma Sa茂d-Hassane ; Sabrina Valetti ; Roseline Gorges ; Val茅rie Nicolas ; Jacques H. Poupaert ; Sylvie Chollet-Martin ; Didier Desma毛le ; Ruxandra Gref ; Patrick Couvreur
- 刊名：ACS Nano
- 出版年：2012
- 出版时间：May 22, 2012
- 年：2012
- 卷：6
- 期：5
- 页码：3820-3831
- 全文大小：641K
- 年卷期：v.6,no.5(May 22, 2012)
- ISSN：1936-086X
文摘
We describe here new nanoparticles based on the bioconjugation of penicillin G to squalene in order to overcome severe intracellular infections by pathogen bacteria whose mechanism of resistance arises from the poor intracellular diffusion of several antibiotics. Two different squalene鈥損enicillin G conjugates were synthesized (pH-sensitive and pH-insensitive), and their self-assembly as nanoparticles was investigated through morphology and stability studies. These nanoparticles had a size of 140 卤 10 nm (polydispersity index of 0.1) and a negative charge, and they did not display any supramolecular organization. Furthermore, they were found stable in water and in different culture medium. The cellular uptake and localization of these fluorescently labeled nanoparticles were explored on the macrophage cell line J774 by flow cytometry and confocal microscopy analysis. The squalenoylated nanoparticles were found to be cell internalized through clathrin-dependent and -independent endocytic pathways. Moreover, they induced an improved intracellular antibacterial activity on the facultative intracellular pathogen S. aureus, compared with free penicillin G, despite the absence of co-localization between the bacteria and the nanoparticles in the cells. This study suggests that the bioconjugation of an antibiotic to a squalene template could be a valuable approach for overcoming the antibiotic resistance due to intracellular bacterial infections.
<h4>Keywords: h4> nanoparticle; squalene; antibiotic; penicillin G; intracellular infections
<h4>Keywords: h4> nanoparticle; squalene; antibiotic; penicillin G; intracellular infections